The goal of this project is to develop a mouse-human chimeric model with a vascular endothelium and a hematopoietic system derived from human induced pluripotent stem (iPS) cells while all other tissues and organs will be from a mouse. Previous reports have demonstrated that making mouse-human chimeras is possible and that human pluripotent and multipotent stem cells are able to respond to the spatial and temporal program of the mouse embryonic environment during development. We believe this is a highly innovative, high-risk proposal with potential high-impact for a broad spectrum of translational and clinical applications. For example, small animal-human chimeric models (e.g. mouse) would be extremely valuable in studies of: (a) leukemia and lymphoma;(b) cardiovascular disease;(c) blood-borne infectious pathogens;(d) vaccine development;and (e) hematopoietic system pathology. PUBLIC HEALTH RELEVANCE: The goal of this project is to develop a new type of animal model which better reflects human disease states and will allow for more rapid development of new drugs through preclinical trials. This model will have high-impact for a broad spectrum of translational and clinical applications.